Identification and in vitro functional assessment of 10 CYP2C9 variants found in Chinese Han subjects

被引:4
|
作者
Zhang, Qing [1 ,2 ,3 ]
Qi, Yuying [4 ,5 ]
Wang, Shuanghu [6 ]
Zhao, Fangling [4 ,5 ]
Zou, Lili [1 ,2 ,4 ]
Zhou, Quan [6 ]
Geng, Peiwu [6 ]
Hong, Yun [2 ,7 ]
Yang, Hang [4 ,5 ]
Luo, Qingfeng [2 ,7 ]
Cai, Jianping [4 ]
Wu, Hualan [1 ,2 ]
Wang, Dongxu [1 ,2 ]
Chen, Hao [1 ,2 ]
Yang, Jiefu [1 ,2 ,3 ]
Dai, Dapeng [4 ]
机构
[1] Beijing Hosp, Natl Ctr Gerontol, Dept Cardiovasc, Beijing, Peoples R China
[2] Chinese Acad Med Sci, Inst Geriatr Med, Beijing, Peoples R China
[3] Chinese Acad Med Sci, Grad Sch, Peking Union Med Coll, Beijing, Peoples R China
[4] Chinese Acad Med Sci, Key Lab Geriatr, Beijing Inst Geriatr, Inst Geriatr Med,Beijing Hosp,Natl Ctr Gerontol,Na, Beijing, Peoples R China
[5] Peking Univ, Beijing Inst Geriatr, Sch Clin Med 5, Beijing, Peoples R China
[6] Wenzhou Med Univ, Peoples Hosp Lishui, Affiliated Hosp 6, Lab Clin Pharm, Lishui, Peoples R China
[7] Beijing Hosp, Natl Ctr Gerontol, Dept Gastroenterol, Beijing, Peoples R China
来源
FRONTIERS IN ENDOCRINOLOGY | 2023年 / 14卷
基金
国家重点研发计划;
关键词
allelic variant; genetic polymorphism; drug metabolism; Chinese Han population; GENETIC-POLYMORPHISM; ALLELIC VARIANT; POPULATION; METABOLISM; ISOFORMS; PHARMACOKINETICS; PHARMACOGENETICS; ASSOCIATION;
D O I
10.3389/fendo.2023.1139805
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Cytochrome P450 2C9 (CYP2C9) participates in about 15% of clinical drug metabolism, and its polymorphism is associated with individual drug metabolism differences, which may lead to the adverse drug reactions (ADRs). In this study, 1163 Chinese Han individuals were recruited to investigate their distribution pattern of CYP2C9 gene and find out the variants that may affect their drug metabolic activities. We successfully developed a multiplex PCR amplicon sequencing method and used it for the genetic screening of CYP2C9 in a large scale. Besides the wild type CYP2C9*1, totally 26 allelic variants of CYP2C9 were detected, which included 16 previously reported alleles and 10 new non-synonymous variants that had not been listed on the PharmVar website. The characteristics of these newly detected CYP2C9 variants were then evaluated after co-expressing them with CYPOR in S. cerevisiae microsomes. Immunoblot analysis revealed that except for Pro163Ser, Glu326Lys, Gly431Arg and Ile488Phe, most of newly detected variants showed comparable protein expression levels to wild type in yeast cells. Two typical CYP2C9 probe drugs, losartan and glimepiride, were then used for the evaluation of metabolic activities of variants. As a result, 3 variants Thr301Met, Glu326Lys, and Gly431Arg almost lost their catalytic activities and most of other variants exhibited significantly elevated activities for drug metabolism. Our data not only enriches the knowledge of naturally occurring CYP2C9 variants in the Chinese Han population, but also provides the fundamental evidence for its potential clinical usage for personalized medicine in the clinic.
引用
收藏
页数:13
相关论文
共 50 条
  • [1] In vitro functional characterization of 37 CYP2C9 allelic isoforms found in Chinese Han population
    Dai, Da-peng
    Wang, Yu-han
    Wang, Shuang-hu
    Geng, Pei-wu
    Hu, Li-ming
    Hu, Guo-xin
    Cai, Jian-ping
    ACTA PHARMACOLOGICA SINICA, 2013, 34 (11) : 1449 - 1456
  • [2] In vitro metabolism of phenytoin in 36 CYP2C9 variants found in the Chinese population
    Chen, Lian-Guo
    Wang, Zhe
    Zhu, Yuan
    Xiong, Jian-Hua
    Sun, Li-Rong
    Dai, Da-Peng
    Cai, Jian-Ping
    Hu, Guo-Xin
    CHEMICO-BIOLOGICAL INTERACTIONS, 2016, 253 : 93 - 99
  • [3] In Vitro and In Vivo Characterization of 13 CYP2C9 Allelic Variants Found in Chinese Han Population
    Hu, Guo-Xin
    Pan, Pei-Pei
    Wang, Zeng-Shou
    Yang, Li-Ping
    Dai, Da-Peng
    Wang, Shuang-Hu
    Zhu, Guang-Hui
    Qiu, Xiang-Jun
    Xu, Tao
    Luo, Jun
    Lian, Qing-Quan
    Ge, Ren-Shan
    Cai, Jian-Ping
    DRUG METABOLISM AND DISPOSITION, 2015, 43 (04) : 561 - 569
  • [4] In vitro functional characterization of 37 CYP2C9 allelic isoforms found in Chinese Han population
    Da-peng Dai
    Yu-han Wang
    Shuang-hu Wang
    Pei-wu Geng
    Li-ming Hu
    Guo-xin Hu
    Jian-ping Cai
    Acta Pharmacologica Sinica, 2013, 34 : 1449 - 1456
  • [5] Effect of 36 CYP2C9 variants found in the Chinese population on losartan metabolism in vitro
    Wang, Yu-Han
    Pan, Pei-Pei
    Dai, Da-Peng
    Wang, Shuang-Hu
    Geng, Pei-Wu
    Cai, Jian-Ping
    Hu, Guo-Xin
    XENOBIOTICA, 2014, 44 (03) : 270 - 275
  • [6] Identification and drug metabolic characterization of four new CYP2C9 variants CYP2C9*72-*75 in the Chinese Han population
    Zhao, Fang-Ling
    Zhang, Qing
    Wang, Shuang-Hu
    Hong, Yun
    Zhou, Shan
    Zhou, Quan
    Geng, Pei-Wu
    Luo, Qing-Feng
    Yang, Jie-Fu
    Chen, Hao
    Cai, Jian-Ping
    Dai, Da-Peng
    FRONTIERS IN PHARMACOLOGY, 2022, 13
  • [7] Impact of CYP2C9 Polymorphism Found in the Chinese Population on the Metabolism of Propofol in Vitro
    Lian, Qing-Quan
    Pan, Pei-Pei
    Li, Jun-Wei
    Lin, Han
    Hu, Guo-Xin
    Zuo, Ming-Zhang
    Cai, Jian-Ping
    BIOLOGICAL & PHARMACEUTICAL BULLETIN, 2015, 38 (04) : 531 - 535
  • [8] Substrate-Dependent Functional Alterations of Seven CYP2C9 Variants Found in Japanese Subjects
    Maekawa, Keiko
    Harakawa, Noriko
    Sugiyama, Emiko
    Tohkin, Masahiro
    Kim, Su-Ryang
    Kaniwa, Nahoko
    Katori, Noriko
    Hasegawa, Ryuichi
    Yasuda, Kazuki
    Kamide, Kei
    Miyata, Toshiyuki
    Saito, Yoshiro
    Sawada, Jun-ichi
    DRUG METABOLISM AND DISPOSITION, 2009, 37 (09) : 1895 - 1903
  • [9] An identification and functional evaluation of a novel CYP2C9 variant CYP2C9*62
    Chen, Hao
    Dai, Da-Peng
    Zhou, Shan
    Liu, Jian
    Wang, Shuang-Hu
    Wu, Hua-Lan
    Zhou, Quan
    Geng, Pei-Wu
    Chong, Jia
    Lu, You
    Cai, Jian-Ping
    Yang, Jie-Fu
    CHEMICO-BIOLOGICAL INTERACTIONS, 2020, 327
  • [10] Identification and Functional Assessment of a New CYP2C9 Allelic Variant CYP2C9☆59
    Dai, Da-Peng
    Wang, Shuang-Hu
    Li, Chuan-Bao
    Geng, Pei-Wu
    Cai, Jie
    Wang, Hao
    Hu, Guo-Xin
    Cai, Jian-Ping
    DRUG METABOLISM AND DISPOSITION, 2015, 43 (08) : 1246 - 1249